Parkinson's disease (PD) is the greatest shared neurodegenerative disease affecting millions of individuals in the world, and it is linked to the continual deterioration of dopaminergic neurons in the Substantia nigra (SN) pars compacta. Despite years of intensive study, the detailed molecular mechanism underlying neuronal loss has not been fully elucidated. Taken together, these findings highlight that oxidative stress is a state of disturbed equilibrium between the creation of reactive oxygen species (ROS) and the activity of antioxidant defense systems within the cells as a key player in triggering and maintaining PD pathology. This review is a systematic one in line with the PRISMA statement. We examined the Scopus, PubMed,  and Web of Science records for published articles in peer-reviewed journals from January 2000 to December 2024. Studies were eligible if they were case-control, cross-sectional, or cohort designs with human subjects, and participants had a confirmed PD diagnosis. In total, 47 articles fulfilling the criteria were included, involving 3,812 PD cases and 2,960 healthy controls. Patients with PD had remarkably increased malondialdehyde and 4-HNE levels, decreased superoxide dismutase and GPx activity, along with a 52.0% reduction in glutathione in SN. High 8-OHdG was significantly linked with UPDRS motor scores (r = 0.61; p < 0.001). There is a strong implication of oxidative stress in the development of PD, and a substantial amount of data supports its involvement in dopaminergic neurodegeneration and α-synuclein toxicity. Peripheral oxidative markers appear to have utility for diagnosis and prognosis. Therapeutic intervention in antioxidant pathways may serve as a potential disease-adapting strategy.